By disrupting waters self-association, co solvents reduce waters ability to squeeze out non-polar, hydrophobic compounds, thus increasing solubility. A different perspective is that by simply making the polar water¹ environment more non-polar like the solute, cosolvents facilitate solubilization. Most co-solvents have hydrogen bond donor and/or acceptor groups as well as small hydrocarbon regions. Action facilitated with alteration of dielectric constant of medium. Their hydrophilic hydrogen bonding groups ensure water miscibility, while their hydrophobic hydrocarbon regions interfere with water hydrogen bonding network, reducing the overall intermolecular attraction of water. By disrupting water self association, co-solvents reduce water ability to squeeze out nonpolar, hydrophobic compounds, thus increasing solubility.

The presence of surfactants may lower the surface tension and increase the solubility of the drug. Poloxamers, gelucire, lecithin, capmul, myrj, labrasol, polysorbate etc. are examples of surface-active carriers used for dissolution enhancement. Surfactants are molecules with distinct polar and nonpolar regions in which hydrocarbon segment is connected to a polar group which may be anionic, cationic, zwitterionic or nonionic. When small apolar molecules are added, they can accumulate in the hydrophobic core of the micelles. This process of solubilization is very important in industrial and biological processes. Surfactants used in certain drug formulations affect P-glycoprotein mediated efflux of drug, leading to altered gastrointestinal tract permeability. Many surfactants such as Vitamin E, Solutol HS 15, Cremophore EL and Polysorbate 80 and oil phases such as Imwitor 742 and Akoline MCM (mono and di-glyceride of caprylic acid) have potential to inhibit P-glycoprotein efflux. Hence, SMEDDS can also inhibit the P-glycoprotein efflux process. To retain a high surface area for the dispersed phase, surface active agents must be used to decrease the surface free energy. Often a mixture of surfactants is used.

Emulsifying agents:

To prevent coalescence, it is necessary to introduce an emulsifying agent that forms a film around the dispersed globules. Surfactants are adsorbed at oil-water interfaces to form monomolecular films and reduce interfacial tensions. A hydrophilic emulsifying agent is needed for the aqueous phase, and a hydrophobic emulsifying agent is needed for the oil phase. A complex film result, which produces an excellent emulsion. Nonionic surfactants are widely used in the production of stable emulsions. They are less toxic than ionic surfactants and are less sensitive to electrolytes and pH variation. Examples include sorbitan esters, polysorbates, and others. Additionally, they increase the viscosity of the dispersion medium. Hydrophilic colloids are used for formation of o/w emulsions since the films are hydrophilic. Most cellulose derivatives are not charged, but can sterically stabilize the systems.

Cyclodextrins of pharmaceutical relevance contain 6, 7 or8 dextrose molecules (α, β, γ-cyclodextrin) bound in a 1, 4- configuration to form rings of various diameters. The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form non covalent inclusion complexes resulting in increased aqueous solubility and chemical stability. Cyclodextrins have a hydrophilic exterior and a hydrophobic internal cavity. This cavity enables cyclodextrins to complex guest drug molecules and hence alters the properties of the drugs such as solubility, stability, bioavailability and toxicity profiles.

Antioxidants:

Antioxidants are included in pharmaceutical solutions or suspensions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation. Typically antioxidants are molecules that are redox systems that exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition. Typically in aqueous solution antioxidants are oxidized (and hence degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition. Both water-soluble and water-insoluble antioxidants are commercially available, the choice of these being performed according to the nature of the formulation have a lower oxidation potential than the active and hence are either preferentially oxidized or block oxidative chain reactions. Injection formulations may, in addition also contain chelating agents, such as EDTA or citric acid, to remove trace elements, which catalyze oxidative degradation. They act by a chain termination by reacting with free radicals. They have a lower redox potential than the drug and get preferentially oxidized, e.g., ascorbic acid. Thus, they can be consumed during the shelf-life of the product radical. E.g. Butylated hydroxyl toluene (True Antioxidants).

Lubricants:

They function by interposing a film of low shear strength at the interface between the tablet and the die wall and the punch face. Lubricants work by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection and also between particles during compression.

Solid lubricants act by two mechanism

1. Boundary mechanism, results from the adherence of the polar portions of molecules with long carbon chains to the metal surfaces to the die wall. Example: Magnesium stearate.

2. Hydrodynamic mechanism i.e. fluid lubrication where two moving surfaces are separated by a finite and continuous layer of fluid lubricant.

Solid lubricants are more effective and more frequently used, because adherence of solid lubricants to the die wall is more than that of fluid lubricants

Presence of lubricants may results in a less cohesive and mechanically weaker tablet because it may interfere with the particle – particle bonding (Lessen tensile strength). Surface area is important parameter for deciding lubricant efficiency. Lubricants with high surface area are more sensitive to changes in mixing time than lubricant with low surface area. Therefore lubricant mixing time should be kept minimum,mixing time in 1 batch production scale is about 3 minutes.

There are three roles identified with lubricants as follows

1. True Lubricant Role

To decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches and dies.

2. Anti-adherent Role

Prevent sticking to punch faces or in the case of encapsulation, lubricants prevent sticking to machine dosators, tamping pins, etc.

3. Glidant Role

They promote and enhance product flow by reducing interparticulate friction.

A good lubricant requirement

1. Low Shear Strength

2. Able to form a “durable layer” over the surface covered.

3. Non-Toxic

4. Chemically Inert

5. Unaffected by Process Variables

6. Posses Minimal Adverse Effects on the Finished Dosage Form.

There are two major types of lubricants

1. Hydrophilic:

Generally poor lubricants, no glidant or anti-adherent properties.

2. Hydrophobic:

Hydrophobic lubricants are generally good lubricants and are usually effective at relatively low concentrations. Many also have both anti- adherent and glidant properties

Disintegrants:

Disintegrating agents are substances routinely included in the tablet formulations to aid in the breakup of the compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet matrix. Their major function is to oppose the efficiency of the tablet binder and the physical forces that act under compression to form the tablet. Their mechanism of action has not been clearly elucidated. The mechanisms proposed in the past include water wicking, swelling, deformation recovery, repulsion, and heat of wetting. It seems likely that no single mechanism can explain the complex behavior of the disintegrants. It acts against binding forces that form mechanical body of tablets. The creation of swelling leads to developing of mechanical pressure within tablet to cause it break apart into small particles. The disintegration efficiency of different particle sizes of crosspovidone, those with the largest particle size range (50–300mm) yielded the shortest disintegration time. Large particle size probably yielded greater pore size and altered the shape of the pore. Indeed, longer fiber length due to greater particle size could improve the efficiency of capillary uptake of water into the dosage form .matrix they were acts by destroying activity of binding agent by enzymatic action and enhance action of capillary forces in producing rapid uptake of aqueous fluids.

Some times their action is facilitated with liberation of gases to disrupt tablet structure. For swelling to be effective as a mechanism of disintegration, there must be a superstructure against which the disintegrant swells. Swelling of the disintegrant against the matrix leads to the development of a swelling force. A large internal porosity in the dosage form in which much of the swelling can be accommodated reduces the effectiveness of the disintegrant. At the same time, a matrix that yields readily through plastic deformation may partly accommodate any disintegrant swelling if swelling does not occur at a sufficient rapidity. The swelling of some disintegrants is dependent on the pH of the media. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Repulsion theory postulates that water penetrates into the tablet through hydrophilic pores and a continuous starch network that can convey water from one particle to the next, imparting significant hydrostatic pressure. The water then penetrates between starch grains because of its affinity for starch surfaces, thereby breaking hydrogen bonds and other forces holding the tablet together.

Humectants:

Humectants are hygroscopic substances generally soluble in water. These ‘‘moisture attractants’’ maintain an aqueous film at the skin surface. The primary used humectants in personal-care products is glycerin; it tends to provide heavy and tacky feel which can be overcome by using it in combination with other humectants such as sorbitol. Less expensive than glycerin, propylene glycol is the second most widely used humectants in cosmetic and toiletry products; it reduces viscosity of surfactant solutions and tends to depress the foam. They are cationic in nature, which makes them absorbing to the negatively charged skin surface. The hydrophilic moiety delivers humectant properties; the hydrophobic chain at the cationic end of the molecule ensures both substantivity and skin conditioning.

Emollients:

Emollients are also described as refatting additives or refatteners in the case of bath products. Emollients function by their ability to remain on the skin surface or in stratum corneum to act as lubricant, to reduce flaking. The word refattener refers to substances improving the lipid content of the upper layers of the skin; they prevent defatting and drying out of the skin. Several emollients showing strong lipophilic character are identified as occlusive ingredients; they are fatty/oily materials that remain on the skin surface and reduce trans epidermal water loss. The CTFA dictionary defines occlusive’s as: ‘‘cosmetic ingredients which retard the evaporation of water from the skin surface; by blocking the evaporative loss of water, occlusive materials increase the water content of the skin.’

Foaming agent:

Foaming agent is an essential property of shampoos, skin cleansers, aerosols, shaving cream, mouthwash, and toothpaste, and its mechanism and stabilization have been studied. Foam is a dispersion of gas bubbles in a liquid and the liquid film of each bubble is colloidal in size. Surfactant solutions often have the important feature of foaminess. This parameter is enhanced by the following :(1) high viscosity in the liquid phase to retard hydrodynamic drainage; (2) high surface viscosity to retard liquid loss between interfaces; (3) surface effects to prevent thinning of liquid film, such as the Gibbs- Marangoni effect; (4) electrostatic and steric repulsion between adjacent interfaces to prevent drainage caused by disjoining pressure; and (5) gas diffusion from smaller to larger bubbles. Foam contains many bubbles separated by liquid films that are continuously enforced by dynamic change in the liquid, such as liquid drainage and bubble motion.

Detergents:

Detergents are more complex and able to clean better in hard water because they do not produce soap scum. Detergents are usually synthetic compounds that originate from crude oil. Detergents have hydrophobic or water-hating molecular chains and hydrophilic or water-loving components. The hydrophobic hydrocarbons are repelled by water, but are attracted to oil and grease. The hydrophilic end of the same molecule means that one end of the molecule will be attracted to water, while the other side is binding to oil. Neither detergents nor soap accomplish anything except binding to the soil until some mechanical energy or agitation is added into the equation. Swishing the soapy water around allows the soap or detergent to pull the grime away from clothes or dishes and into the larger pool of rinse water.

Defoamers:

Defoamers were insoluble in the foaming medium and have surface active properties. An essential feature of a defoamer product is a low viscosity and a facility to spread rapidly on foamy surfaces. It has affinity to the air-liquid surface where it destabilizes the foam lamellas. This causes rupture of the air bubbles and breakdown of surface foam. Entrained air bubbles are agglomerated, and the larger bubbles rise to the surface of the bulk liquid more quickly, leading to the rupture of the film surface and air escape.

Preservatives: They will impart it action by alter cell membrane permeability causing leakage of cell constituent (partialysis), complete lysis, and cyto plasmic leakage or coagulation of protein. Inhibit cellular metabolism by interfere with enzyme systems or cell wall synthesis, oxidation of cellular constituents or hydrolysis.

Plasticizers: They intend to interpose between every individual strands of polymer and there by breaking polymer –polymer interactions. It imparts soften and swell polymers which aids in overcoming their resistance to deformulation. plasticizer polymers would deforms at lower tensile force as compared to without plasticizer . This enhances film elongation effect, addition of plasticizers decreases glass transition temperature. Few time it will acts internal lubricant s by minimizing frictional force by interspersing themselves between polymeric chains. These will modify physical and mechanical properties of film by enhancing mobility of polymeric chains.

Buffering agents:

After getting equilibrium between acids and bases favors little a changing in concentration of acids and bases, so therefore solution is buffered buffer agents set up this concentration ratio by providing corresponding conjugate acid or base to stabilize .pH of that which it is added to. They are buffer to a low capacity so that buffers of blood may readily bring them within physiologic pH range.

Wetting agent:

Wetting agent is a chemical compound that reduces the surface tension of a liquid. The surface tension of a liquid is the tendency of the molecules of a liquid to bond together and is determined by the strength of the bonds between the liquid’s molecules. A wetting agent stretches these bonds and decreases the tendency of molecules to hold together, which allows the liquid to spread more easily across any solid surface.

Wetting agents account for surface activity of molecule. It acts by decreasing in surface free energy as a result of immersion process and spreading of wetting occurs. They reduce contact angle and improve dispersion of powder. They are absorbed at solid liquid interface and increases affinity of particles towards liquid medium and decreases forces between particles. Presences of air over solid particles were replaced by liquid at the surface when dissolved in water. Excess presence of wetting agents leads to generation of foam and initiation of bad odour and taste.

A wetting agent can also be known as a surfactant, which is a type of chemical that alters the properties of liquid, because it causes changes to the surface tension of the liquid. Surfactants can also contain dispersants, which are chemicals that separate oil and water, and emulsifiers, which combine oily liquids with water. Wetting agents can be made up a variety of chemicals, all of which have this tension-lowering effect. When the wetting agent is applied, it causes the liquid to create particles called micelles, which allow the penetration of the solid by the liquid. Micelles are made up of molecules that attract water and molecules that repel water. In water, the micelles assemble in a large cluster where the water-attracting molecules form a ring with the water-repelling molecules in the center. When the wetting agent is used in oily liquids, the structure of this micelle is reversed as the water-repelling molecules are on the outside of the ring because they are attracted to the oily liquid and the water-attracting molecules are repelled by the oily liquid. These chemical compounds are very useful in decreasing surface tension of water and spreading the water over the solid surfaces that it comes into contact with, such as clothing, skin and hair. Some wetting agents are actually used inside the human body. Laxatives are just one example of a wetting agent used internally. Since dehydration of the intestinal tract can often cause constipation adding a wetting agent can help solve this problem by applying water to the impacted intestinal material. Toothpaste can also contain wetting agents, although swallowing toothpaste is generally not recommended.

Harsher chemical compound examples of wetting agents may include pesticides, herbicides and insecticides. Wetting agents are used in these products to allow the other harmful chemical agents in these products to penetrate the solid they are applied to.

Surfactants:

They show characteristic solubility because of the presence of hydrophobic groups, which squeeze out hydrocarbon chains of surfactants to bring about micelle formation. Soaps and detergents work because they contain surfactants. A surfactant is any molecule that reduces water tension and bonds to dirt. Once the dirt and surfactants are bonded, the rinse water washes the surfactants away, taking dirt and grime with it. Synthetic surfactants bond to particles because they hold a charge. Depending on the surfactant used, when mixed with water it can take on a positive or negative charge. Most surfactants used in detergents and soaps become positively charged when mixed with water. Surfactants lower the surface tension of water, essentially making it 'wetter' so that it is less likely to stick to itself and more likely to interact with oil and grease.

The emulsifying agent stabilises the emulsion by adsorbing at the liquid–liquid interface as an oriented interfacial film. This film reduces the interfacial tension between the liquids and also decreases the rate of coalescence of the dispersed droplets by forming mechanical, steric and or electrical barriers around them. A strong mechanical barrier lessens the chance of droplets coalescing on collision. For maximum mechanical stability, the interfacial film of the adsorbed surfactants should be close packed with strong lateral interactions. For this reason, a mixture of two or more surfactants is commonly used as the emulsifying agent. In the micelle, the molecular environment of the drug molecules changes their proximity and orientation with respect to each other, which may affect activity. In a micelle, the drug molecules may be protected from attacking species such as hydronium or hydroxide ions and the stability of the drug may be increased.

The solubilizing capacity for a given surfactant system is a complex function of the physicochemical properties of the two components which, in turn, influence the location or sites where the drug is bound to the micelle. The molar volume of the solubilizate together with its lipophilicity is important factors, the former reducing and the latter increasing solubilization. Many pharmaceutical products contain a number of solutes potentially capable of being solubilized within the micellar phase. Thus competition can occur between solutes resulting in an altered solubilizing capacity. Furthermore, the addition of a second highly solubilized component to form a mixed micellar system may greatly alter the structure, size and solubilizing.

Bitter masking agents:

The complexing agent is capable of masking the bitter taste of a drug by either decreasing its oral solubility on ingestion, or decreasing the amount of drug particles exposed to taste buds, thereby reducing the perception of bitter taste. The inclusion complexes with cyclodextrin owing their existence to van-der Waals forces between the host and guest. Granulation lowers the effective surface area of the bitter substance that comes in contact with the tongue upon oral intake. Liquids and low melting point waxes such as glycerol palmito stearate, glyceryl behenate and hydrogenated castor oil are commonly used ingredients. Sodium alginate has the ability to cause water insoluble gelation in presence of bivalent metal ions. Tablets of amiprolose hydrochloride have been taste masked by applying an undercoat of sodium alginate and over coat of calcium gluconate. In presence of saliva, sodium alginate reacts with bivalent calcium and forms water insoluble gel and thus taste masking achieved. Types of microencapsulation include^2,3,4air suspension coating ,coacervation phase separation, spray drying and spray congealing were also advanced techniques by which this property provide.

Increasing the viscosity with rheological modifier such as gums or carbohydrates can lower the diffusion of bitter substances from the saliva to the taste buds. This provides a taste masked liquid preparation for administration of a relatively large amount of unpleasant tasting medicines. Potentiators increase the perception of the taste of sweeteners and mask the unpleasant taste. Various potentiators include thaumatine, Neohesperidine dihydro chalcone (NHDC) and glycyrrhizin increase the perception of sodium or calcium saccharinates, saccharin, cyclamates etc.

Molecular geometry of the substrate is important for the taste receptor adsorption reaction i.e., mechanism of taste. Hence if any alteration is done in molecular geometry, it lowers the adsorption rate constant. Thus taste masking can be achieved through prodrug^5-7 approach.

REFERENCES:

1. R. K. Maheshwari, S. C. Chaturvedi, N. K. Jain, Novel spectrophotometric estimation of some poorly water soluble drugs using hydrotropic solubilizing agents, Asian J. Pharm. Clin. Res., Volume 3, Issue 10, 2010, 43-45.

2. Shalini Sharma., Shaila Lewis., Taste masking technologies: a review., International Journal of Pharmacy and Pharmaceutical Sciences,2010; 2(2):6- 13

3. Zelalem Ayenew., Vibha Puri., Lokesh Kumar., Arvind K. Bansal., Trends in Pharmaceutical taste masking technologies: A patent review., Recent Patents on Drug Delivery & Formulation, 2009;3:26-39

4. Chatap V K. A Review on Taste Masking Methods of Bitter Drugs. Pharmainfo.net

5. Sinkula, A.A., Yalkowsky, S.H. J. Pharm. Sci. 1975; 64: 200‐203.

6. Brahamnkar, D.M., Jaiswal, S.B. Prodrugs. In Biopharmaceutics And Pharmacokinetics; A

7. Treatise. Vallabh Prakashan. Delhi; 1998. P163.

8. James Swarbrick, Encyclopedia of Pharmaceutical Technology, volume 1,third edition.P3553.

Received on 23.07.2013

Modified on 18.08.2013

Accepted on 21.08.2013

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(6): November-December, 2013, 355-360